Skyclarys
omaveloxolone
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”
Why that species
Monkey chosen as non-rodent because dogs develop species-specific GI toxicity with the related compound bardoxolone methyl
“Monkeys were chosen as the non-rodent non-clinical species in the omaveloxolone testing programme as dogs have previously been shown to develop species-specific gastrointestinal toxicity following repeated dosing with the chemically related substance, bardoxolone methyl.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Male and female cynomolgus monkeys (9-10/sex/group) were administered doses of 0 (sesame oil), 10, 30, or 100 mg/kg RTA 408 by daily oral gavage for 39 weeks with 4 weeks recovery;”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey oral studies
“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Route in tox
Oral (gavage)
“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames; positive in vitro chromosomal aberration (human lymphocytes); negative in vivo rat micronucleus and comet assays
“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”
Carcinogenicity
2-year rat: increased liver cholangioma/cholangiocarcinoma in high-dose females (1.9x human AUC)
“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”
Reproductive & developmental
Developmental toxicity (embryofetal death, growth impairment, offspring mortality and neurobehavioral deficits) at or below clinical exposure
“In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans”
Safety pharmacology
Monkey single oral doses up to 100 mg/kg: no effects on blood pressure, heart rate or ECG including QTc
“Cardiovascular endpoints were assessed in cynomolgus monkeys administered single oral doses of RTA 408 up to 100 mg/kg. There were no drug effects on body temperature, blood pressure, heart rate, or ECG (PR, RR, QRS, and corrected QT intervals).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Skyclarys don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat (FDA pharmacology/toxicology review, p. 4)
NOAEL / key findings
Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat
“Based on the liver (bile duct hyperplasia) and kidney (tubular degeneration/regeneration) findings at all doses (0, 0.3, 1, or 3 mg/kg) in the 26-week study, a NOAEL was not established in rats.”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; not required for this small molecule
“Considering the type of molecule (small molecule), investigations of antigenicity and immunotoxicity are not required for omaveloxolone.”
Biodistribution & persistence
~3.41% oral bioavailability in monkey; wide tissue distribution including brain, highest in GI tract
“Following oral administration to monkeys, [14C]RTA 408 was approximately 3.41% bioavailable and was widely distributed to most tissues, including brain, between 8 and 30 h, with the highest concentrations observed in the gastrointestinal tract.”
Modality-specific risk
Major human metabolite M22 inadequately covered in rat and monkey general and reproductive toxicity studies (MIST)
“Therefore, M22 was not adequately tested in the general toxicology studies in rat and monkey or in any reproductive and developmental toxicology studies in rat.”